78 J.Org. Chern., V d . 44, No. 1, 1979
Harvey, Lee, and Shyamasundar
Synthesis of the Dihydrodiols and Diol Epoxides of Benzo[ elpyrene and Triphenylene Ronald G. Harvey,* Hong Mee Lee, and N. Shyamasundar Ret1 M a y Laboratory f o r Cancer Research, L'nicersiiy of C'i7icago, C'hicago,Illinois 60637
Received Fpbruary 17, 1978 Syntheijis of t h e "bay region" dihydrodiols of benzo[e]pyrene and triphenylene ( 1 and 2) and the corresponding anti isomeric diol epoxides (3 and 4) is described. NMR analysis indicates 1-4 exist preferentially in the diaxial conformation in contrast to t h e analogous derivatives of t h e potent carcinogen benzo[a]pyrene shown previously t o exist preferentially as the diequatorial conformer. Both 3 and 4, derived from hydrocarbons inactive as carcinogens, are inactive as inhibitors of the rbX 174 DNA virus, whereas the analogous anti-diol epoxide of benzo[n Jpyrene is highly potent in this respect.
trans -7,8-Dihydroxy-anti-9,lO-epoxy-7,8,9,lO-tetrahydrometabolism of carcinogens and noncarcinogens. Specifically, benzo[a]pyrene ( a n t i - B P D E ) has been strongly implicated it is of some importance to determine: (a) whether these by several lines of evidence as the metabolically activated form dihydrodiols and diol epoxides can be formed by cells; (b) of b e n ~ o [ a ] p y r e n e ,a~potent carcinogen widespread in the whether the latter are capable of alkylation of nucleic acids environment.2 Other recent studies point to analogous diol in vitro and in vivo; and (c) whether they are biologically active epoxide metabolites as the active forms of S-methylcholanas mutagens, carcinogens, inhibitors of viral replication, etc. threne,6 benz[a]anthracene (BA),73 7-methylbenz(a]anthracene: 7,12-dimethyl benz[~]anthracene,~OJl chrysene,12J'i Results However, 5-methyl~hrysene,l'~ and dibenz[~,h]anthracene.~s Three synthetic routes to the trans -9,lO-dihydrodiol of ReP synthesis of these and other diol epoxides urgently required ( 1 ) were explored. A key intermediate in all three was transfor biological studies has been achieved in only a few cases. Although the synthetic approaches initially devised for synand anti-BPDE16h,ave subsequently been modified and imScheme I. Synthesis of trans-9,lO-dihydrobenzo[ e Ipyrene (1)
5
proved4J7J8 and extended to other polycyclic arene~,~,l3,~7-19 the syntheses remain relatively complex, complicated by the special problems cd isolation and purification of relatively reactive molecule^.^ T h e present report describes the synthesis of the transdihydrodiols (1 and 2) and anti-diol epoxides ( 3 and 4) of benzo[e]pyrene (Rep) and triphenylene. While both 3 and 4
6
8 5%
7
or{
8
n
10
9 1
L
OH
11
3
4
are close structural analogues of anti-BPDE, the parent hydrocarbons are considered to be inactive as carcinogens.20 Consequently, these compounds are of interest f o r biological studies to determine differences, if any, in the patterns of
12
12%
BzO"
0022-3263/79/1944-0078$01.00/0e 1979 American Chemical Society
13
Dihydrodiols of Benzo[e]pyrene
J . Org. Chem., Vol. 44, No. 1, 1979 79
Scheme 11. Alternative! Synthesis of trans-9,lO-Dihydroxy9,10,11,12-tetrahydrobenzo[ e Ipyrene Dibenzoate (11)
assignment. T h e relatively small value of J S ,(2~Hz) ~ is consistent with a trans-diequatorial relationship between these protons.22Treatment of 13 with sodium methoxide in methanol cleaved t h e benzoate ester groups to furnish the free dihydrodiol 1 as a white solid, m p 185-186 "C. T h e 1H N M R spectrum of 1 exhibited benzylic, allylic, vinylic, and aromatic protons in t h e anticipated ratio, closely resembling the analogous region of the spectra of other trans-dihydrodiols.4T h e 100-MHz spectrum of the diacetate of 1 was nicely resolved 14 with signals at 6 5.47 (Hlo),6.57 HI^), 7.05 (Hg),and 7.81 ( H I ? ) l i5.6, and J l l , i r with appropriate couplings J9,10 = 2.2, J l , l ,.= = 10.5 Hz, consistent with this assignment. Finally, epoxidation of 1 with rn-chloroperbenzoic acid afforded the antidiol epoxide 3 as a white solid. An alternative synthetic route to 11 involving aromatization prior to cyclization was also investigated (Scheme 11).Dehy15 16 drogenation of the methyl ester of 6 over a 10% Pd/C catalyst a t 220 "C afforded smoothly methyl y-(4-pyrenyl)butyrate A (14), m p 59-60 "C, in 93% yield. T h e NMR spectrum of 1 1 revealed aromatic, methylene, and methyl protons in the anticipated 9:6:3 ratio. Cyclization of 1.1 in polyphosphoric acid directly afforded the 9-keto derivative of 9,10,11,12-tetrahydrobenzo[e]pyrene (151, isolated virtually quantitatively from chromatography on Florisil as a yellou crystalline solid, 17 m p 132-133 "C. Reduction of 15 with Na13H4, followed by 9,10-dibenzoyloxy-9,10,11,12-tetrahydrobenzo[e]pyrene acid-catalyzed dehydration, provided 9,10-dihydrot)enzo[e]pyrene (17),m p 123-124 "C ( 1 k 2 , ' j 124-126 "C'1. This structure (11). Synthesis of the latter was accomplished in optimum overall was supported by the NMR spectrum, which exhihited a pair yield (58%) from [j-(1,2,3,6,7,8-hexahydro-4-pyrenoyl)pro-of vinylic peaks at d 6.38 ( d o f t ) and 7.40 i d ) assigned t o H I pionic acid (5) via the sequence depicted in Scheme I. Com, l'1lHz) and HI^, respectively; the observed couplings ( J ! , l= pound 5 was itself synthesized from pyrene through reduction were in accord with this assignment. Methylene. vinylic, and with sodium and alcohol followed by condensation with sucaromatic protons were also observed in the expected ratio (2:2:8). Finally, PrCvost reaction of 17 furnished pure 11, m p cinic anhydride according to the method of Cook and Hewett.21 Reduction of 5 by t h e Huang-Minlon modification of 215-216 "C, whose NMR spectrum was identical with that of the Wolff-Kishner method gave the reduced acid 6, cyclizathe dibenzoate of trans-9,10-dihydroxy-9,10,11.12-tetrahvtion of which in liquid H F provided the ketone 7. Yields were drobenzo[e]pyrene synthesized by the met hod in Scheme I. 98 and 85%, respectively, marked improvements over those T h e overall yield of 11 from 6 via the seqrienc'e i n Scheme I1 reported in t h e older literature" (52 and 29%, respectively) was 68%. by other methods. Reduction of the carbonyl group of 7 with T h e third synthetic approach to 1 1 explored involved synNaBH4 furnished essentially quantitatively the corresponding thesis of 9,10-dihydrobenzo[e]pyrenefrom the parent hyalcohol 8. Acid-catalyzed dehydration of the latter afforded drocarbon via catalytic hydrogenation t o 9,10,11,12-tetrahydrobenzo[e]pyrene followed by dehydrogenation with cleanly 1,2,3,6,7,8,9,10-octahydrobenzo[e]pyrene (91, m p DDQ. This method, described in a preliminary communica129-130 "C; this structural assignment was supported by the tion,2.' provides an efficient synthetic approach to a variety integrated proton N M R spectrum, notably the HI1 and HI:! of dihydroarenes. In the present case, however, yields from vinyl proton peaks a t 6 6.20 and 6.80, respectively. PrCvost both steps proved somewhat erratic and difficult t o control reaction of 9 by the procedure utilized in our previous studies4 gave t h e corresponding trans-diol dibenzoate 10. T h e latter and purification of products presented additional problems. was converted smoothly to 11 on treatment with excess DDQ Iintil these problems can be solved, this method is not recommended for synthesis of 1 I. in refluxing benzene. T h e integrated proton NMR spectrum Synthesis of 1,2-dihydrotriphenylene (21 I. the dihydroarene of 11 was in agreement with this structural assignment, which required as precursor of the trans-1,2-dihydrodiol of triwas further confirmed by microanalysis and by the identity of t h e melting point (219-220 "C) and other physical propphenylene (21, was accomplished via a sequence analogous to erties with those of the dibenzoate prepared by the alternative route outlined in Scheme 11. Conversion of 11 t o t h e required dihydrodiol(1j and antidiol epoxide of B e P (3) was accomplished by t h e general method previously utilized for the synthesis of analogous c o m p ~ u n d s . ~ Jl 9~Bromination J~ of 11 with NBS in C C 4 afforded a mixture of stereoisomeric bromodibenzoates (12) in 18 19 high yield (99%). Since bromo compounds of this type are notoriously thermally unstable, no attempt was made to separate the isomers by fractional crystallization. Instead, the mixture was dehydrohrominated directly with D B N to trans-9,10-dibenzoyloxy-9,lO-dihydrobenzo[e]pyrene ( 13). T h e 60-MHz N M R spectrum of 13 was consistent with this structural assignment exhibiting characteristic allylic (Hlo) and vinylic ( H l l )peaks a t 6 5.98 and 6.75, respectively; the H9 and H12 benzylic and vinylic proton signals were obscured 21 20 somewhat by the aromatic protons, preventing their accurate
n
i
80 J . Org. Chem., Vol. 44, No. I , 1979
Harvey, Lee, and Shyamasundar
that in Scheme 11. T h e intermediate keto compound, 1keto-1,2,,3,4-tetrahydrotriphenylene (20), required for this purpose was synthes,ized from 9-bromophenanthrene through reaction of the corresponding Grignard reagent with succinic anhydride, followed by Clemmensen reduction and cyclization of the resulting acid 19 in liquid HF. T h e overall yield of 20 obtained via this sequence was superior t o t h a t reportedly obtained through a irelated sequence involving Wolff-Kishner reduction of the semicarbazone of 18 and cyclization of 19 with phosphoric oxide.24Reduction of 20 with NaBH4 followed by acid-catalyzed dehydration of the resulting alcohol furnished 1,2-dihydrotriphen,ylene (21), m p 116 "C; this structural assignment was supported by microanalysis and by the integrated NMR spectrum, which exhibited aromatic, vinylic, benzylic, and allylil: protons in the expected ratios. T h e H4 vinylic proton appeared downfield in the aromatic region as a consequence of steric interaction with t h e aromatic peri hydrogen a t the 5 position. This downfield shift is characteristic of bay region p r o t ~ n s ,and ? ~ was also seen for t h e hydro:gen atoms in th'? 5, 8, 9, and 12 positions. T h e remaining appeared as a well-resolved multiplet a t vinylic proton, Hi{, 8 625 coupled to the HJ, CH:{,and H I protons ( J : I =, ~10 Hz; J:,:
